This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goals of this project are 1) to investigate the survival and function of porcine islet xenografts in rhesus macaques using a novel costimulation blockade-based regimen 2) to prolong islet xenograft survival by optimizing new and existing costimulation blockade-based immunosuppressive therapies and testing new methods and sites of islet implantation. Using pancreatectomized macaque recipients, neonatal islets, and a costimulation-blockade based regimen targeting the CD40L pathway, our lab had excellent initial success with porcine islet transplantation, achieving long-term graft survival, function, and insulin independence. However, the clinical usefulness of anti-CD40L reagents was limited by significant incidence of thromboembolic complications. Building on these results, we have turned our attention to alternative immunosuppressive regimens targeting other costimulation pathways such as CD40 and CD28. We have had encouraging, though somewhat inconsistent, results with these regimens, which in some cases provided excellent xenograft survival. Current and future directions will focus on more clinically applicable reagents such as Tacrolimus and LFA-3Ig. Islets from pigs bred to lack the surface carbohydrate Gal on all tissues (Gal-KO) may circumvent the robust innate immune response that is usually mounted against transplanted xenogeneic tissues. Initial results investigating the transplantation of Gal-KO islets under cover of costimulation blockade-based regimens have been extremely good;these experiments are ongoing. Each experiment employs significant Yerkes resources including veterinary staff, rhesus monkeys, operating room time and staff, and pathology services.